General anesthesia is a drug-induced, reversible condition comprising five behavioral states: hypnosis (loss of consciousness), amnesia, analgesia, and immobility (no movement in response to pain stimuli), and hemodynamic stability with control of the stress response. Anesthetics such as ketamine are used to provide all of the above behavioral states. Neuromuscular blocking agents (NMBAs) are used to provide immobility (muscle relaxation) in anesthetized patients, as part of conventional medical procedures where administration of anesthesia is required. For example, NMBAs are used to enable safe endotracheal intubation for administration of anesthesia. They are also used to facilitate access of surgeons to body cavities without the risk of voluntary or reflex muscle movements which if left unchecked can compromise the precision required for such interventions. NMBAs can also be used in the care of patients for whom mechanical ventilation is necessary, but sedation and analgesia alone are inadequate to render the patient amenable to insertion and/or ongoing operation of a suitable ventilation apparatus.
Pharmacological reversal of the effects of NMBAs is typically used at the end of surgery. Currently in the U.S. all approved reversal agents are acetylcholinesterase inhibitors which inhibit metabolism of acetylcholine. However, these inhibitors have many side effects, such as bradycardia, hypersalivation, hypotension, and bronchospasm. While some of these undesirable effects can be alleviated by co-administration of muscarinergic acetylcholine receptor agonists, such as atropine, the co-administered agents themselves can also trigger unwanted effects, such as blurred vision, dry mouth and tachydardia. Furthermore, acetylcholinesterase inhibitors can only be used when neuromuscular activity has already recovered to 10% of normal activity, but deeper muscle blocks cannot be reversed by acetylcholinesterase inhibitors. While sugammadex, a cyclodextrin molecule that encapsulates an inactivates steroidal NMBAs has been used in some countries for reversal of rocuronium and vecuronium induced neuromuscular block, use of this agent in the U.S. was curtailed by the Food and Drug Administration because of severe allergic reactions and coagulation abnormalities induced by it. In addition, benzylisoquinoline-type NMBA compounds, which represent about 30% of the current market volume for NMBA, cannot be reversed by sugammadex. Moreover, it is not possible with any available drug to reverse benzylisoquinoline-type NMBA (e.g., atracurium or cisatracurium). Additionally, although the actions of many drugs used in anesthesiology are reversed pharmacologically when no longer desired (e.g., NMBAs, opioids, benzodiazepines), this is not the case for general anesthetic induced loss of consciousness. Thus, there is an ongoing and unmet need for improvements in reversal of drug-induced neuromuscular block.